|Coordinate||140,885,945 bp (GRCm38)|
|Base Change||T ⇒ C (forward strand)|
|Gene Name||caspase recruitment domain family, member 11|
|Synonym(s)||CARMA1, BIMP3, 2410011D02Rik, 0610008L17Rik|
|Chromosomal Location||140,872,990-141,000,582 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene belongs to the membrane-associated guanylate kinase (MAGUK) family, a class of proteins that functions as molecular scaffolds for the assembly of multiprotein complexes at specialized regions of the plasma membrane. This protein is also a member of the CARD protein family, which is defined by carrying a characteristic caspase-associated recruitment domain (CARD). This protein has a domain structure similar to that of CARD14 protein. The CARD domains of both proteins have been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. When expressed in cells, this protein activated NF-kappaB and induced the phosphorylation of BCL10. [provided by RefSeq, Jul 2008]
PHENOTYPE: Mice homozygous for a targeted null mutation exhibit defects in antigen receptor signalling in both T and B lymphocytes. [provided by MGI curators]
|Amino Acid Change||Glutamine changed to Arginine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000082941]|
AA Change: Q667R
|Predicted Effect||possibly damaging
PolyPhen 2 Score 0.755 (Sensitivity: 0.85; Specificity: 0.92)
|Meta Mutation Damage Score||0.09|
|Is this an essential gene?||Non Essential (E-score: 0.000)|
|Candidate Explorer Status||CE: not good candidate; human score: -3; ML prob: 0.376|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Semidominant|
|Last Updated||2019-09-04 9:41 PM by Diantha La Vine|
|Record Created||2016-12-08 8:38 AM|
The Tumnus phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R4889, some of which showed an increased frequency of B1 cells (Figure 1) in the peripheral blood.
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 51 mutations. The increased frequency of B1 cells was linked by continuous variable mapping to a mutation in Card11: an A to G transition at base pair 140,885,945 (v38) on chromosome 5, or base pair 114,652 in the GenBank genomic region NC_000071 encoding Card11. Linkage was found with an additive model of inheritance to the normalized frequency of B1 cells, wherein eight variant homozygotes and 28 heterozygous mice departed phenotypically from 21 homozygous reference mice with a P value of 1.799 x 10-7 (Figure 3).
The mutation corresponds to residue 2,321 in the mRNA sequence NM_175362 within exon 16 of 25 total exons.
The mutated nucleotide is indicated in red. The mutation results in a glutamine (Q) to arginine (R) substitution at position 667 (Q667R) in the CARMA1 protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 0.755).
CARMA1 contains no catalytic domains, but several protein interaction domains [Figure 3; reviewed in (1)]. The N-terminal half of CARMA1 contains a caspase recruitment domain (CARD) (residues 19-105) and a coiled-coil domain (residues 116-439). A membrane-associated guanylate kinase (MAGUK) domain occupies the bulk of the C-terminal half of CARMA1 (2;3). MAGUK family proteins contain 3 modular protein interaction domains, of which the hallmark is an approximately 300 amino acid region with homology to yeast guanylate kinase (GUK), but which is catalytically inactive. In addition, up to three PDZ domains and an SH3 domain are always present in tandem with the guanylate kinase domain. CARMA1 contains one PDZ (residues 660-742), one SH3 (residues 766-834) and one GUK domain (residues 954-1142) (2;3). The N- and C-terminal halves of CARMA1 are connected by a region of 232 amino acids between the CARD and coiled-coil domains designated the linker domain (residues 440-671). A NORS (no regular secondary structure) subdomain is found at the N-terminus of the linker domain (residues 44-519). The Tumnus mutation results in a glutamine (Q) to arginine (R) substitution at position 667 (Q667R) in CARMA1; residue 667 is within the PDZ domain.
Please see the record for king for more information about Card11.
CARMA1 belongs to the membrane-associated guanylate kinase (MAGUK) protein family, whose members function as molecular scaffolds for the localized assembly of such multiprotein complexes [reviewed in (4)]. Upon T cell activation by the T cell receptor (TCR) and costimulatory molecule engagement, CARMA1 associates with a complex containing Bcl10 and MALT1 (Mucosa-Associated Lymphoid tissue lymphoma Translocation-associated gene 1; also known as MLT or Paracaspase) and recruits these proteins to lipid rafts of the immunological synapse, where they activate the IKK complex, leading to degradation of IκB and subsequent activation of NF-κB (5-8). The CARMA1/Bcl10/MALT1 complex functions similarly in B cells to activate NF-κB in response to BCR engagement (9). NF-κB controls the proliferation, differentiation and survival of B and T cells by activating the transcription of target genes, including various cytokines.
CARMA1 mutants have normal numbers and differentiation of B cells in the bone marrow, but IgDhighIgMlow splenocytes and serum immunoglobulins (IgM, IgG1, IgG2a, IgG2b, IgG3, and IgA) are reduced in CARMA1 mutants. Peritoneal CD5+ B1 B cells are absent, and NK cells are reduced in number in CARMA1 mutant mice. CARMA1 mutant B cells fail to proliferate in response to BCR stimulation with anti-IgM, or upon CD40 stimulation. T cell development is largely normal in CARMA1 mutants, which have normal numbers of single- and double-positive thymocytes. However, within the double negative (CD4-CD8-) compartment, the proportion of DN3 cells (CD25+CD44lo) is reduced, while that of DN4 cells (CD25-CD44lo) is increased. Activating mutations in CARD11 (e.g., Gly123Asp, Glu127Gly, and Gly116Ser) have been linked to a disorder in humans associated with persisten polyclonal B cell lymphocytosis [PPBL; OMIM: #606445; (10;11). PPBL is also often referred to as B cell expansion with NF-κB and T-cell anergy (BENTA). PPBL onset occurs in infancy with patients exhibiting splenomegaly and polyclonal expansion of B cells, subsequently leading to peripheral lymphocytosis (11). PPBL patients may also exhibit mild immune dysfunction (e.g., defective antibody responses and T cell anergy) as well as the development of B cell malignancy (11). Patients with B cell lymphocytosis exhibit high expression of cell cycle progression genes as well as increased proliferation and improved B cell survival after BCR stimulation (10).
1) 94°C 2:00
The following sequence of 400 nucleotides is amplified (chromosome 5, - strand):
1 gaatccctta gaacccagag gcctccaagc ctcaaggaca catacagcca tgccaccagc
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Thome, M. (2004) CARMA1, BCL-10 and MALT1 in Lymphocyte Development and Activation. Nat Rev Immunol. 4, 348-359.
2. Bertin, J., Wang, L., Guo, Y., Jacobson, M. D., Poyet, J. L., Srinivasula, S. M., Merriam, S., DiStefano, P. S., and Alnemri, E. S. (2001) CARD11 and CARD14 are Novel Caspase Recruitment Domain (CARD)/membrane-Associated Guanylate Kinase (MAGUK) Family Members that Interact with BCL10 and Activate NF-Kappa B. J Biol Chem. 276, 11877-11882.
3. Gaide, O., Martinon, F., Micheau, O., Bonnet, D., Thome, M., and Tschopp, J. (2001) Carma1, a CARD-Containing Binding Partner of Bcl10, Induces Bcl10 Phosphorylation and NF-kappaB Activation. FEBS Lett. 496, 121-127.
4. Funke, L., Dakoji, S., and Bredt, D. S. (2005) Membrane-Associated Guanylate Kinases Regulate Adhesion and Plasticity at Cell Junctions. Annu Rev Biochem. 74, 219-245.
5. Gaide, O., Favier, B., Legler, D. F., Bonnet, D., Brissoni, B., Valitutti, S., Bron, C., Tschopp, J., and Thome, M. (2002) CARMA1 is a Critical Lipid Raft-Associated Regulator of TCR-Induced NF-Kappa B Activation. Nat Immunol. 3, 836-843.
6. Egawa, T., Albrecht, B., Favier, B., Sunshine, M. J., Mirchandani, K., O'Brien, W., Thome, M., and Littman, D. R. (2003) Requirement for CARMA1 in Antigen Receptor-Induced NF-Kappa B Activation and Lymphocyte Proliferation. Curr Biol. 13, 1252-1258.
7. Che, T., You, Y., Wang, D., Tanner, M. J., Dixit, V. M., and Lin, X. (2004) MALT1/paracaspase is a Signaling Component Downstream of CARMA1 and Mediates T Cell Receptor-Induced NF-kappaB Activation. J Biol Chem. 279, 15870-15876.
8. Wang, D., You, Y., Case, S. M., McAllister-Lucas, L. M., Wang, L., DiStefano, P. S., Nunez, G., Bertin, J., and Lin, X. (2002) A Requirement for CARMA1 in TCR-Induced NF-Kappa B Activation. Nat Immunol. 3, 830-835.
9. Sommer, K., Guo, B., Pomerantz, J. L., Bandaranayake, A. D., Moreno-Garcia, M. E., Ovechkina, Y. L., and Rawlings, D. J. (2005) Phosphorylation of the CARMA1 Linker Controls NF-kappaB Activation. Immunity. 23, 561-574.
10. Brohl, A. S., Stinson, J. R., Su, H. C., Badgett, T., Jennings, C. D., Sukumar, G., Sindiri, S., Wang, W., Kardava, L., Moir, S., Dalgard, C. L., Moscow, J. A., Khan, J., and Snow, A. L. (2014) Germline CARD11 Mutation in a Patient with Severe Congenital B Cell Lymphocytosis. J Clin Immunol. .
11. Snow, A. L., Xiao, W., Stinson, J. R., Lu, W., Chaigne-Delalande, B., Zheng, L., Pittaluga, S., Matthews, H. F., Schmitz, R., Jhavar, S., Kuchen, S., Kardava, L., Wang, W., Lamborn, I. T., Jing, H., Raffeld, M., Moir, S., Fleisher, T. A., Staudt, L. M., Su, H. C., and Lenardo, M. J. (2012) Congenital B Cell Lymphocytosis Explained by Novel Germline CARD11 Mutations. J Exp Med. 209, 2247-2261.
|Science Writers||Anne Murray|
|Authors||Xue Zhong and Bruce Beutler|